Project Abstract/Summary Functional recovery of an injured axon in the brain is one of the central challenges of neuroscience. To date, most attention concerning axon injury and repair has focused on neurons in the spinal cord, retinal ganglion cells, and the dorsal root ganglion; knowledge about axonal injury and repair in neurons from the brain, particular in GABAergic interneurons, is limited. Although GABAergic interneurons are a small population in the brain, they are crucial for the control of inhibition. Previous studies have shown that spinal interneurons survive well after axotomy, and axotomized spinal interneurons develop axon-like processes that cross the midline. There are multiple subtypes of interneurons in the cerebral cortex, but little is known about the regenerative capacity of their axons in an injured brain. The challenge in axonal repair studies in the brain is to distinguish the contribution of the intrinsic properties of neurons from that of environmental cues. We thus propose to establish an optogenetic approach for axotomy in different interneuron subtypes (Aim I) and characterize the potential for axonal repair in GABAergic interneurons in the mouse brain (Aim II). Our central hypothesis is that different GABAergic interneuron subtypes in the cerebral cortex will have different potential to repair their axons after axotomy. We will transect their axons upon illumination of miniSOG332 with blue-light in both juvenile and adult mice and directly image axonal repair from days to months to determine regeneration potential. Our long-term goal is to study interneuron injury and repair in the brain and find ways to promote repair. The results will greatly improve our understanding of neuronal repair in traumatic brain injury or stroke. The identification of mechanisms underlying interneuron repair will assist the design of new therapeutic approaches for the treatment of traumatic brain injury and stroke.